Process for producing dihydronaphthalene derivatives

ABSTRACT

2-(1&#39;-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula ##STR1## is produced by reducing 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula, ##STR2## with a reducing agent obtained by reacting one equivalent of lithium aluminum hydride with one equivalent of an optically active N-substituted ephedrine of the formula, ##STR3## (wherein R 1  is a C 1  -C 4  alkyl group or benzyl group, and Ph is phenyl group) and two equivalents of an N-substituted aniline of the formula, ##STR4## (wherein R 2  is a C 1  -C 4  alkyl group or phenyl group, and Ph is phenyl group).

This is a division of application Ser. No. 238,136 filed Feb. 25, 1981and now U.S. Pat. No. 4,338,255.

This invention relates to a novel reducing agent which can be used forreducing the organic compounds haing a carbonyl group (ketone group oraldehyde group) in their structure into the corresponding alcohols andwhich is particularly useful as a reducing agent for asymmetricallyreducing the unsymmetrical ketones to selectively give an alcohol inwhich the asymmetric carbon atom bonded to the hydroxy group is inR-configuration or an alcohol in which said asymmetric carbon atom is inS-configuration. That is, the invention relates to a novel lithiumaluminum hydride type reducing agent partially decomposed by using oneequivalent of an optically active N-substituted ephedrine and twoequivalents of an N-substituted aniline. More particularly, thisinvention relates to a novel modified lithium aluminum hydride typereducing agent obtained by reacting one equivalent of lithium aluminumhydride with one equivalent of an optically active N-substitutedephedrine of the formula (I), ##STR5## (wherein R₁ is a C₁ -C₄ alkylgroup or benzyl group, and Ph is phenyl group) and two equivalents of anN-substituted aniline of the formula (II), ##STR6## (wherein R₂ is a C₁-C₄ straight chain alkyl group or phenyl group, and Ph is phenyl group).

The optically active N-substituted ephedrine represented by theabove-shown formula (I) is either a (-)-isomer or a (+)-isomer. The C₁-C₄ alkyl group represented by R₁ in the above-shown formula (I) may beproperly selected from the straight chain or branched chain alkyl groupssuch as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, iso-butyl,sec-butyl, etc., but the methyl group is preferred. As for the C₁ -C₄alkyl group represented by R₂ in the above-shown formula (II), there maybe recited the straight chain alkyl groups such as methyl, ethyl,propyl, butyl, etc., but a methyl or ethyl group is preferred, thelatter being more preferred.

There are known a number of reagents capable or reducing the carbonylgroup of an organic compound having a ketone structure (>C═O) or analdehyde structure ##STR7## into a hydroxy group. As such reagents,there may be recited, for example, sodium borohydride, potassiumborohydride, lithium borohydride, zinc borohydride, sodiumcyanoborohydride, lithium aluminum hydride, lithiumtri-tertbutoxyaluminum hydride, lithium tri-methoxyaluminum hydride,sodium bis(2-methoxyethoxy)aluminum hydride, sodium aluminum hydride,etc. However, when an unsymmetrical ketone reducing reaction isperformed by using such reducing agents, the resulting product becomesan equal-weight mixture, namely a racemate, of an alcohol in which theasymmetric carbon atom bonded to the hydroxy group is R-configurationand an alcohol in which said asymmetic carbon atom is inS-configuration. In contrast with this, when an unsymmetrical ketonereducing reaction is conducted by using the reducing agent of thisinvention, there takes place an asymmetric reduction to allow muchstereo-selective formation of either an alcohol in which the asymmetriccarbon atom bonded to the hydroxy group is in R-configuration or analcohol in which said asymmetric carbon atom is in S-configuration.

Many efforts have been made toward development of the reagents forasymmetric reduction of unsymmetrical ketones. Particularly, lots oftests have been pursued on the modified lithium aluminum hydridesformulated by partially decomposing lithium aluminum hydrides with anoptically active compound, and some asymmetrical reducing reagents withgood selectivity have been worked out. However, any of the hithertoproposed reagents has some defects as mentioned below.

For example, Vigneron et al have worked out a modified lithium aluminumhydride partially decomposed by using N-methyl-ephedrine and3,5-dimethylphenol (I. Jacquet and J. P. Vigneron: Tetrahedron Letters,1974, 2065; J. P. Vigneron and I. Jacquet: Tetrahedron, 32, 939 (1976);J. P. Vigneron and V. Bloy: Tetrahedron Letters, 1979, 2683; Idem.,Ibid., 1980, 1735), but this preparation involves the followingproblems. The 3,5-dimethylphenol used as additive is bound to mix in thereduction product alcohol and difficult to separate. Also, its reducingpower is weak, and reduction of an α,β-unsaturated ketone, aldehyde orthe like results in a poor chemical yield.

Another modified lithium aluminum hydride partially decomposed with aproline derivative has been worked up by Mukaiyama et al (T. Mukaiyama,M. Asami, J. Hanna and S. Kobayashi: Chemistry Letters, 1979, 783; M.Asami, H. Ohono, S. Kobayashi and T. Mukaiyama: Bull. Chem. Soc. Japan,51, 1869 (1978); M. Asami and T. Mukaiyama: Heterocycles, 12, 499(1979)), but this preparation has defects that the proline used asasymmetry source is expensive and that several steps are required forthe synthesis thereof.

Also lately, a modified lithium aluminum hydride partially decomposedwith a binaphthyl alcohol derivative and an alcohol was proposed byNoyori et al (R. Noyori, I. Tomino and Y. Tanimoto: J. Am. Chem. Soc.101, 3129 (1979); R. Noyori, I, Tomino and M. Nishizawa: Ibid., 101,5843 (1979)), but this proposal has the drawbacks that the asymmetrysource must be synthesized and resolved, that difficulties attend theseparation of the reduction product alcohol and that its chemical yieldis poor.

The present inventors have devoted themselves to the study aimed atovercoming the above-shown problems and working out an excellentmodified lithium aluminum hydride type reducing agent which can meet allof the following three requirements:

1. The reduction reaction proceeds with a high chemical yield and a highasymmetry yield.

2. The yielded alcohol product can be easily separated from theasymmetry source and other additives used.

3. The asymmetry source used is available in large quantities and at lowcost, and it can be also easily recovered with a high optical purity andin a high yield after completion of the reaction and can be reused.

As a result, the present inventors have found an excellent modifiedlithium aluminum hydride type reducing agent which is free of thedefects of the conventional modified lithium aluminum hydride typereducing agents and which meets all of the above-said three requirementsand is commercially practiceable, and completed the present invention.

The reducing agent acording to this invention can be obtained byreacting one equivalent of lithium aluminum hydride with one equivalentof an optically active N-substituted ephedrine of the afore-showngeneral formula (I) and two equivalents of an N-substituted anilinerepresented by the afore-shown general formula (II).

The reaction is carried out under an anhydrous condition in anatmosphere of an inert gas such as nitrogen or argon gas.

The reaction solvent used in the process of this invention is notsubject to any specific restrictions provided that it does not take anypart in the reaction, and there may be used, for example, a solvent suchas dimethyl ether, diethyl ether, tetrahydrofuran, diglyme, methylal,toluene or the like, but among them, diethyl ether is preferred.

The reaction can be safely conducted at a temperature of from 0° to 100°C., but it is recommended to use a temperature of from room temperatureto 40° C.

The reaction time is not specifically limited, and a one- to three-hourreaction will suffice.

The N-methylephedrine represented by the general formula (I) wherein R₁is a methyl group can be easily synthesized by a one-step treatment onlycomprising reductive methylation of a corresponding readily accessibleunexpensive (+)- or (-)-ephedrine with formaline-formic acid (K.Nakajima: Journal of the Chemical Society of Japan, 81, 1476 (1960)).

The lithium aluminum hydride employed for the preparation of suchmodified lithium aluminum hydride type reducing agents is usually usedin the form of a solution, but according to the present invention, it isnot necessarily used as a solution; it can as well be used as asuspension in a reaction solvent, which widens the industrialversatility of the process of this invention.

The thus obtained modified lithium aluminum hydride type reducing agentsaccording to this invention are believed to have a chemical structureexpressed by the following formula (III), ##STR8## (wherein R₁, R₂ andPh are as defined above).

The reducing agent of this invention prepared in the manner describedabove is usually not isolated from the reaction solution but isimmediately used for the ensuing reduction reaction.

The reducing agent of this invention is usable as a reducing agent forconverting the carbonyl group in an organic compound having a ketone oraldehyde structure into a hydroxy group. It is specifically noteworthythat the product of this invention can be used as an asymmetricreduction agent for the unsymmetrical ketones, namely, the compoundshaving a ketone structure which produces the asymmetric center as aresult of reduction.

In the course of the reduction of an organic compound, there takes placeno side reaction and the carbonyl group alone is reacted even if suchcompound has in its structure a functional group such as ester,carboxylic acid, amide, olefin or the like, so that the product of thisinvention can be applied to all sorts of organic compounds having aketone or aldehyde structure. The preferable organic compounds are theunsymmetrical ketone compounds having a ketone structure which producesthe asymmetric center as a result of the reduction.

The reduction employing the reducing agent of this invention is carriedout by using said reducing agent and an organic compound having a ketoneor aldehyde structure under anhydrous conditions in an atmosphere of aninert gas such as nitrogen or argon gas.

The amount of the reducing agent of this invention used in the reactionmay be of any ratio greater than one equivalent to one equivalent of theorganic compound, but a ratio of 1-5 equivalents to one equivalent ofthe organic compound is preferred.

The reaction solvent used in this invention is not subject to anyspecific restrictions provided that it does not participate in thereaction. There may be used, for example, dimethyl ether, diethyl ether,tetrahydrofuran, diglyme, methylal, toluene, etc., but diethyl ether ispreferred.

The reaction temperature is within the range of -100° to 100° C., and atemperature of from -78° to -100° C. is preferred for an asymmetricreduction reaction.

The reaction time, although not limited specifically, may be 1 to 6hours.

After performing the reduction reaction under the above-said conditions,the reaction solution is added with an aqueous solution of a mineralacid such as hydrochloric acid or sulfuric acid and the organic solventlayer is separated, followed by drying and distilling-off of the organicsolvent, whereby the desired alcohol compound alone can be readilyobtained in a high yield.

The optically active N-substituted ephedrine (I) and N-substitutedaniline (II) used in the reaction can be recovered as a mixture in analmost quantitative yield by merely adding an alkaline aqueous solutionsuch as an aqueous sodium hydroxide solution or an aqueous potassiumhydroxide solution to the above-said aqueous layer, extracting the mixedsolution with an organic solvent such as ethyl acetate, etc. which candissolve the optically active N-substituted ephedrine (I) andN-substituted aniline (II), then drying the extract and distilling offthe organic solvent. Also, they can be recovered separately by means ofdistillation under reduced pressure.

In this way, the N-substituted ephedrine (I) can be recovered in anoptical purity without accompanying racemization and can be reused as itis.

As an embodiment of use of the reducing agent of this invention, it isused in a reaction for obtaining2-(1'-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula(V), ##STR9## by reducing the carbonyl (>CO) portion of2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula (IV),##STR10##

In the case of the reducing agent of this invention using a (-)-isomer((-)-1(R),2(S)-N(C₁ -C₄) alkyl- or benzyl-substituted ephedrine) as theN-substituted ephedrine of the formula (I), such reducing agent may beused for performing an asymmetric reduction of the compound of theformula (IV) to give(-)-2-(1'(S)-hydroxy)-ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of theformula (V'), ##STR11## This asymmetric reduction is performed at -78°C. for 3 hours and the neutral portion is separated from the reactionproduct to obtain a crude compound of the formula (V'). Also,(-)-N-methylephedrine and N-ethylaniline are recovered quantitativelyfrom the basic portion of the reaction product.

Recrystallization of the crude compound (V') from n-hexane gives thecompound (V') of 100% optical purity, m.p.: 88°-89° C., [α]_(D) ²⁰-20.5° (C=1.07, ethanol).

Examples of (-)-N-(C₁ -C₄) alkyl- or benzyl-substituted ephedrinesusable for the preparation of said reducing agent of this invention are(-)-N-methylephedrine, (-)-N-ethylephedrine (O. Cervinka, et al: Coll.Czech Chem., Comm., 32, 3897 (1967)), (-)-N-propylephedrine,(-)-N-isobutylephedrine, (+)-N-benzylephedrine (S. Yamada et al:Yakugaku Zasshi, 100, 319 (1980)). Among them, (-)-N-methylephedrine isthe most preferred asymmetry source. As examples of N-mono-(C₁ -C₄)alkyl- or benzyl-substituted anilines, one may recite, besideN-ethylaniline, the following: N-methylaniline, N-propylaniline,N-isopropylaniline, N-butylaniline, N-isobutylaniline,N-ethyl-3,5-dimethylaniline, N-ethyl-2,6-dimethylaniline, diphenylamine,carbazole, etc., but the asymmetry yield of the compound (V') was bestwhen N-ethylaniline was used. In case of using n-t-butylaniline,pyrrolidine, piperidine, morpholine, pyrrole, imidazole, benztriazole orthe like in place of N-ethylaniline, there took place no desiredreduction reaction or, even though the reaction advanced, the asymmetryyield was low.

The compound of the formula (V) (particularly (V')) is an intermediateproduct in the course of the preparation of2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol of the formula (1),##STR12## particularly,(-)-2(R)-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2(R)-naphthol of theformula (1'), ##STR13## The compound of the formula (1) or (4') is onewhich is extraordidnarily useful as a material for the synthesis of theanthracycline type antibiotics adriamycin (2), daunorubicin (3), etc.,which are attracting keen interest lately in their prominentcarcinostatic activities (F. Arcamone: Lloydia, 40, 45 (1977); T. R.Kelly: "Synthetic Approaches to Anthracycline Antibiotics" in "AnnualReports in Medicinal Chemistry," Am. Chem. Soc., 1979). From thecompound of the formula (1'), there can be synthesized adriamycinone (4)and daunomycinone (5) which are the aglycones of (2) and (3),respectively. Also, there has been established a route for the synthesisof (2) and (3) from the aglycones (4) and (5), respectively (C. M. Wong,et al: Can. J. Chem., 49, 2712 (1971); C. M. Wong, et al: Ibid., 51, 466(1973); T. H. Smith, et al: J. Org. Chem., 42, 3653 (1977)). Further,4-demethoxy adriamycin (6) and 4-demethoxy daunorubicin (7), which arethe non-natural type anthracyclines with few unfavorable side effectssuch as cardiac trouble, can be synthesized by using the compound (1')as starting material (F. Arcamone, et al: Cancer Treat. Rep., 60, 829(1976); F. Arcamone, et al: German Offen. 2,601,785; F. Arcamone:Lloydia, 40, 45 (1977)).

As stated above, the compound of the formula (1), particularly (1'), isa very important compound as a starting material for the preparation ofnatural and non-natural type anthracyclines.

As explained above, the reducing agent of this invention can serve as auseful reagent in the first step of a process for producing a compoundof the formula (1) or (1') effectively by using the compound of theformula (IV) as a starting material.

A process for obtaining the compound of the formula (1) or (1') from thecompound of the formula (V) or (V') is shown below by way of reference.

The double bond between 1-position and 2-position of the compound of theformula (V) or (V') is epoxidized to form2-(1'-hydroxy)ethyl-5,8-dimethoxy-1,2-epoxy-1,2,3,4-tetrahydronaphthaleneor 2(S)-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-1(S),2(S)-epoxy-1,2,3,4-tetrahydronaphthalene of the formula (VI) or (VI'),##STR14## Then, the 1,2-epoxy portion ##STR15## of this compound isreduced to obtain2-(1'-hydroxy)ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol or(-)-2(R)-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-3(R)-naphtholof the formula (VII) or (VII'), ##STR16## and then the 1'-hydroxyportion (>CHOH) of this compound is oxidized to obtain the compound ofthe formula (1) or (1').

The ordinary double bond epoxidation reaction formula ##STR17## used forthe 1-position and 2-position double bond epoxidation reaction in thefirst stage of the above-said process. As the oxidizing agent, there maybe ordinarily used a reagent prepared from t-butylhydroperoxide,cumenehydroperoxide, etc., in the presence of a catalyst such asmolybdenum dioxyacetylacetonate (MoO₂ (acac)₂), vanadiumoxyacetylacetonate (VO(acac)₂), etc. (K. B. Scharpless et al: J. Am.Chem. Soc., 95, 6136 (1973); H. Yamamoto, et al: Bull. Chem. Soc. Japan,52, 1701 (1979)) as well as the organic peracids such as perbenzoicacid, m-chloroperbenzoic acid, peracetic acid, etc. Usually, thereaction is carried out in an aromatic hydrocarbon solvent such asbenzene, toluene, etc. or a halogenated hydrocarbon solvent such aschloroform, methylene chloride, etc., at a temperature of -20° to +20°C. for a period of 30 minutes to 4 hours.

Since the compound (VI) obtained in this reaction is unstable, it isusually immediately passed on as a crude compound to the ensuing stepwithout refining.

When the compound of the formula (V') having 100% optical purity isoxidized in a solvent such as benzene, etc. by using a reagent preparedfrom t-butylhydroperoxide in the presence of vanadium oxyacetylacetonate(catalyst), there can be obtained an optically active compound (VI').Usually, such compound is obtained as a mixture with small quantities ofits 1(R)-, 2(R)- isomers (see Referential Example), and since thismixture is an unstable oil, it is immediately subjected to the ensuingstep without refining.

The reduction reaction of the 1,2-epoxy portion of the compound (VI) inthe second stage can be accomplished by a usual reduction reaction of anepoxy ##STR18## into an alcohol ##STR19## This reaction is performed inan ether type solvent such as tetrahydrofuran, etc. or an aromatichydrocarbon type solvent such as benzene, toluene, etc., by usingusually lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminumhydride or the like as reducing agent at a temperature of -20° to +25°C. for a period of 1-4 hours.

When the optically active compound (VI') is subjected to this reductionreaction, there is obtained an optically active compound of the formula(VII'). When the above-said reduction reaction is carried out by usingthe compound (VI') mixed with small quantities of 1(R), 2(R) isomers,there is normally obtained a compound (VII') mixed with a 2(S)-epimer,but this crude product can be refined by means of column chromatography,recrystallization, etc. Said compound, in the form of a mixture with a2(S)-epimer, may be immediately subjected to the succeeding oxidationreaction.

The oxidation of the 1'-hydroxy portion (>CHOH) of the compound (VII) inthe third step is usually accomplished by using the method of oxidizinga secondary alcohol into a corresponding ketone (>CHOH→>C═O). As theoxidizing agent, there is usually used chromic acid-sulfuric acid,pyridinium chlorochromate (E. J. Corey, et al: Tetrahedron Letters,1975, 2647), dimethylsulfoxide-dicyclohexylcarbodiimide-trifluoroaceticacid-pyridine (K. E. Pfitzner, et al: J. Am. Chem. Soc., 87, 5661, 5670(1965)), silver carbonate-Celite (Fetizon reagent) (Fetizon, et al: J.Org. Chem., 36, 1339 (1971)), dimethylsulfoxide-sulfur trioxide (SO₃)pyridine complex-triethylamine (J. R. Parikh, et al: J. Am. Chem. Soc.,89, 5505 (1967)) or the like, and the reaction is usually accomplishedin a solvent such as acetone, dichloromethane, dimethylsulfoxide,benzene, etc., at a temperature of 0°-80° C. for a period of 1-24 hours.

Oxidation of the optically active compound (VII') by use of the Fetizonreagent provides the optically active compound (1') of this invention.When the compound (VII') mixed with 2(S)-epimer as said above is used,there is obtained the compound (1') mixed with 2(S)-epimer.

As described above, after reducing2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene (IV) by using the reducingagent of this invention to obtain the compound (V) or (V') andsubjecting this reduced compound to a simple reaction operation whichcan be practiced industrially, there can be obtained2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol (1) which can serveas a very useful starting material for the synthesis of theanthracycline antibiotics. It is particularly noteworthy that theoptically active body (1') of the compound (1) can be obtained in 100%optical purity. The compound of the formula (IV) can be readily preparedfrom 5,8-dimethoxy-3,4-dihydro-2-naphthoic acid (S. Terashima, et al:Chem. Pharm. Bull., (Tokyo), 27, 2351 (1979)).

It is to be noted here that the compound (1) includes 2(R)-body,2(S)-body or mixtures thereof, compound (V) includes 1'(S)-body,1'(R)-body or mixtures thereof, compound (VI) includes1'(S),1(S),2(S)-body, 1'(S),1(R),2(R)-body, 1'(R),1(R),2(R)-body,1'(R),1(S),2(S)-body or mixtures of optional combinations of theses fourtypes of isomers, and compound (VII) includes 1'(S),2(R)-body,1'(S),2(S)-body, 1'(R),2(S)-body, 1'(R),2(R)-body and mixtures ofoptional combinations of these four types of isomers. Concerning theprocess of (IV→V→VI→VII→1), there exist the following relations:##STR20##

The present invention is described in further detail hereinbelow withreference to the examples, but the present invention is not limited tothese examples.

EXAMPLE 1 Synthesis of (-)-N-methylephedrine

Ephedrine hydrochloride (30.3 g, 0.15 mol) was dissolved in warm water(60 ml) there was, then added thereto a 40% sodium hydroxide aqueoussolution (15 ml, 0.15 mol) and 85% formic acid (21.7 g, 0.4 mol) and themixtures refluxed under heating, and to this solution was added dropwisea 35% formalin solution (15 g, 0.18 mol) over 20 minutes. Thereafter,refluxing under heating was continued for 3 hours and the reactionsolution was concentrated to 1/2 of its original volume and then addedthereto was a 40% sodium hydroxide aqueous solution to adjust the pH toabout 11. The resultant precipitated crystals were filtered out andrecrystallized from methanol. Yield: 23 g (84%); m.p.: 86.5°-87.5° C.[α]_(D) ²⁰ =-29.5° (C=4.54, MeOH).

EXAMPLE 2

Preparation of modified lithium aluminum hydride type reducing agent

Dry ether (10 ml) was added into lithium aluminum hydride (206 mg, 5.4mmol) in an argon atmosphere and the mixture was refluxed under heating,mixed with a dry ether (10 ml) solution of (-)-N-methylephedrine (1 g,5.56 mmol) and reacted under stirring at the same temperature for onehour. To this reaction solution was further added a dry ether (10 ml)solution of N-ethylaniline (1.35 g, 11.12 mmol) to perform reactionunder stirring at the same temperature for one hour, whereupon a totalof 363 ml of hydrogen gas was generated and an ether solution of amodified lithium aluminum hydride type reducing agent having thefollowing physical properties was obtained.

IR absorption spectrum (neat): ν; 3420, 2960, 1780, 1600, 1500, 1450,1380 cm⁻¹.

EXAMPLE 3 Reduction of acetophenone

The reaction solution of Example 2 was cooled to -78° C., added theretowas a dry ether (10 ml) solution of acetophenone (360 mg, 3 mmol) andthe mixture reacted under stirring at the same temperature for 3 hours.

After the reaction was over, 1 N hydrochloric acid (24 ml) was added toseparate the ether layer and this ether layer was washed with 10%hydrochloric acid (20 ml) and a saturated saline solution (20 ml×3),then dried with anhydrous magnesium sulfate and filtered, and thefiltrate was concentrated under reduced pressure to obtain(S)(-)-1-phenylethanol. Yield: 330 mg (90%), [α]_(D) ²⁰ =-36.4° (C=7.45,cyclopentane), optical purity: 84%.

The aqueous layer and the 10% hydrochloric acid washings were joined andthe joined solution was mixed with a 10% sodium hydroxide solution (30ml) to adjust the pH to about 11 and extracted with ethyl acetate (50ml×3). The extract was washed with a saturated saline solution (50ml×3), dried and then ethyl acetate was distilled off to obtain amixture of N-methylephedrine and N-ethylaniline. Yield: 2.4 g (100%).Said two substances can be recovered, separately by distilling themixture under reduced pressure.

N-methylephedrine: b.p.: 120° C./0.01 mmHg;

yield: 850 mg, [α]_(D) ²⁰ =-29.0° (C=6.50, MeOH).

N-ethylaniline: b.p.: 87°-90° C./15 mmHg,

yield: 1.3 g.

EXAMPLE 4

Various ketone compounds were reduced in the same way as in Example 3 toobtain the results as shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                              Yield   Optical purity                                  Run    Substrate      (%)     (%), (R, S)                                     ______________________________________                                                ##STR21##     96      90(S)                                           2                                                                                     ##STR22##     95      78(S)                                           3                                                                                     ##STR23##     100     80(S)                                           4                                                                                     ##STR24##     88      71(S)                                           5                                                                                     ##STR25##     96      51(S)                                           6                                                                                     ##STR26##     98      67(R)                                           7                                                                                     ##STR27##     90      41(S)                                           8                                                                                     ##STR28##     90      35(S)                                           ______________________________________                                    

EXAMPLE 5 Reduction of benzylideneacetone

Dry ether (10 ml) was added to lithium aluminum hydride (376 g, 9.9mmol) in an argon atmosphere, and the mixture was refluxed underheating, mixed with a dry ether (20 ml) solution of(-)-N-methylephedrine (1.83 g. 10.2 mol) and reacted under stirring atthe same temperature for one hour. To this reaction solution was added adry ether (10 ml) solution of N-ethylaniline (2.47 g, 20.4 mmol) and itwas further reacted under stirring at the same temperature for one hour.

The reaction solution was cooled to -78° C., added with a dry ether (5ml) solution of benzylideneacetone (439 mg, 3 mmol) and reacted understirring at the same temperature for 3 hours. After completion of thereaction, 1 N hydrochloric acid (42 ml) was added to separate the etherlayer and the ether layer was washed with 1% hydrochloric acid (20 ml×2)and a saturated saline solution (20 ml×3), dried with anydrous magnesiumsulfate and filtered, and the filtrate was concentrated under reducedpressure to obtain (S)(-)-benzylideneisopropanol. Yield: 435 mg (98%),[α]_(D) ²⁰ =24.2° (C=5.16, CHCl₃), optical purity: 98%.

EXAMPLE 6

Various ketone compounds were reduced in the same way as in Example 5.The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                               Yield     Optical purity                               Run     Substrate      (%)       (%) (R.S.)                                   ______________________________________                                                 ##STR29##     100       >90*                                         2                                                                                      ##STR30##     100       >90*                                         3                                                                                      ##STR31##     100       92(S)                                        4                                                                                      ##STR32##     92        78(S)                                        5                                                                                      ##STR33##     58        32(S)                                        6                                                                                      ##STR34##     73        58*                                          7                                                                                      ##STR35##     88        24*                                          8                                                                                      ##STR36##     88        76(S)                                        ______________________________________                                         *: Optical purity was measured by using an NMR shift reagent                  (Eu(hfc).sub.3).                                                         

EXAMPLE 7

Lithium aluminum hydride (1.44 g, 38 mmol) was suspended in ether (70ml) under an argon stream, and to this suspension was added an ethersolution (100 ml) of (-)-N-methylephedrine (6.81 g, 38 mmol), followedby refluxing under heating and stirring for one hour, further additionof an ether solution (60 ml) of N-ethylaniline (9.21 g, 76 mmol) andrefluxing under heating and stirring for an additional one hour tothereby prepare a reducing reagent was conducted.

EXAMPLE 8 Preparation of(-)-2-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene (V')

An ether solution of the reducing reagent of Example 7 was cooled to-78° C., added thereto slowly was an ether solution (200 ml) of thecompound (IV') (2.20 g, 9.47 mmol) and the product was reacted understirring at the same temperature for 3 hours. Upon completion of thereaction, the reaction mixture was mixed with 1 N hydrochloric acid (152ml, 152 mmol) and extracted with ethyl acetate (150 ml×2). The obtainedextracts were joined, washed with a 1% hydrochloric acid aqueoussolution (150 ml×2), a 5% sodium bicarbonate solution (150 ml), water(150 ml×2) and a saturated saline solution (150 ml) in that order andthen dried with anhydrous magnesium sulfate. The resulting product wasfiltered and distilled to obtain the crude compound (V') in the form oflight yellow crystals (2.58 g, quantitative yield), [α]_(D) ²⁰ =-17.8°(C=1.83, ethanol).

Supposing that the optical purity of the compound (V') with [α]_(D) ²⁰=-20.5° (C=1.07, ethanol) obtained by subjecting the above-said sampleto the following operation is 100%, the optical purity of said sample is87%. Recrystallization of the obtained crystals from hexane (130 ml)gave the colorless needlelike crystals of the pure compound (V') with100% optical purity (yield: 1.8 g, 81%; m.p.: 88°-89° C.; [α]_(D) ²⁰=-20.5° (C=1.07, ethanol)). IR: ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 3600,1260, 1100 (alcohol). NMR (in CDCl₃)δ: 1.32 (3H, d, J=6 Hz, CH(OH)CH₃),2.00-2.36 (2H, m, CH₂ C═), 2.12 (1H, s, OH), 2.64-2.88 (2H, m, CH₂ CH₂C═), 3.74 (6H, s, two OCH₃), 4.40 (1 H, q, J=6 Hz, CH(OH)), 6.60 (2H, s,aromatic protons), 6.72 (1H, brs, ═CH). Anal.: Calcd. for C₁₄ H₁₈ O₃ :C, 71.77, H, 7.74, Found: C, 71.57, H, 7.76.

The 1 N hydrochloric acid layer remaining after extraction with ethylacetate was made alkaline (pH>12) with a 10% sodium hydroxide aqueoussolution and extracted with ethyl acetate (150 ml×2). The ethyl acetateextracts were joined, washed with a saturated saline solution (150 ml)and dried with anhydrous potassium carbonate, followed by filtration anddistillation to obtain a 1:2 mixture of (-)-N-methylephedrine andN-ethylaniline as a light yellow oily product (16.3 g, quantitativerecovery).

EXAMPLE 9 Preparation of the compound (1') by using the compound (V') asa starting material

(1)(-)-2(R)-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2(R)-naphthol(VII'):

The compound of the formula (V') (m.p.: 88°-89° C., [α]_(D) ²⁰ =-20.5°(C=1.07, ethanol)) (703 mg, 3.00 mmol) and vanadium oxyacetylacetonate(11 mg, 0.042 mmol) were dissolved in benzene (55 ml) under an argonstream, and the mixed solution was mixed with a benzene solution oft-butylhydroperoxide (22 mg/ml, 13.5 ml, 3.3 mmol) at room temperatureunder stirring and reacted at the same temperature for 1.5 hours. Uponcompletion of the reaction, benzene was distilled off to obtain amixture of crude compound (VI') and 1(R),2(R) isomer thereof as anunstable oily product. This product was dissolved in tetrahydrofuran (40ml) and this tetrahydrofuran solution was added to a suspension oflithium aluminum hydride (456 mg, 12 mmol) in tetrahydrofuran (40 ml),and the suspension was stirred at room temperature for 2 hours. Uponcompletion of the reaction, the reaction mixture was mixed with a 10%sodium hydroxide aqueous solution (65 ml) and the water layer wasextracted with ethyl acetate (50 ml×3). The extracts were joined, washedwith water (50 ml×3) and a saturated saline solution (100 ml) and driedwith anhydrous magnesium sulfate. The resulting product was filtered anddistilled to obtain a mixture of crude compound (VII') and 2(S)-epimerthereof in the form of colorless crystals (730 mg, 97% from (V')).

A part (380 mg) of the colorless crystals (730 mg) was separated andrefined by column chromatography (silica gel, solvent; benzene-ethylacetate (1:1)) to obtain a mixture of the compound (VII') and its2(S)-epimer as colorless needle-like crystals (325 mg, 82% from (V')),m.p.: 140°-150° C., [α]_(D) ²⁰ =-39.3° (C=1.04, ethanol). Both IR andNMR spectra of this product agreed with those of the pure compound(VII') shown below. Since the compound (1') with 90% optical puritycould be obtained from said product, the ratio of the compound (VII') toits 2(S)-epimer, that is, the ratio of the compound (VI') to its1(R),2(R)-epimer was calculated to be 95:5.

The remainder (350 mg) of said colorless crystals (730 mg) wascrystallized from ether (35 ml) to obtain the pure compound (VII') inthe form of colorless needle-like crystals (252 mg, 70%), m.p.:154°-155° C., [α]_(D) ²⁰ =-49.7° (C=0.50, ethanol). IR ν_(max)^(CHCl).sbsp.3 cm⁻¹ : 3580, 1260, 1105, 1090 (alcohol). IR ν_(max)^(KBr) cm⁻¹ : 3360, 1260, 1085 (alcohol). NMR (in CDCl₃ -CD₃ OD)δ: 1.23(3H, d, J=6 Hz, CH(OH)CH₃), 1.40-2.05 (2H, m, CH₂ C(OH)), 2.50-2.88 (4H,m, CH₂ C(OH)CH₂ CH₂), 3.20 (2H, s, OHX2), 3.62 (1H, q, J=6 Hz,CH(OH)CH₃), 3.72(3H, s, OCH₃), 3.74 (3H, s, OCH₃), 6.60 (2H, s, aromaticprotons). Anal.: Calcd. for C₁₄ H₂₀ O₄ : C, 66.64, H, 7.99, Found: C,66.48, H, 8.06.

(2) (-)-2(R)-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2(R)-naphthol (1'):

A mixture of the compound (VII') and its 2(S)-epimer showing (m.p.:140°-150° C., [α]_(D) ²⁰ =-39.3° (C=1.04, ethanol)) (135 mg, 0.54 mmol)was dissolved in benzene (13 ml), then mixed with Fetizon reagent (1mmol/g, 2.7 g, 2.7 mmol) and refluxed under heating for 30 minutes.After the completion of the reaction, silver-Celite was filtered out andwashed with benzene (40 ml). The washed solutions were joined and thefiltrate was concentrated under reduced pressure to obtain a reddishbrown oily product (140 mg). This product was separated and refined bythin-layer chromatography (silica gel, solvent: benzene-ethyl acetate(5:1)) to obtain the compound (1') as colorless crystals (105 mg, 84%),m.p.: 123°-127° C., [α]_(D) ²⁰ =-42.5° (C=0.89, chloroform). The IR andNMR spectra of this product agreed with those of the pure preparationshown below. Supposing that the optical purity of the compound (1') with[α]_(D) ²⁰ of -47.1° (C=1.11, chloroform) is 100%, then the opticalpurity of this product is 90%.

A similar treatment was performed on the pure compound (VII') m.p.:154°-155° C., [α]_(D) ²⁰ =-49.6° (C=1.08, ethanol)) (134 mg, 0.53 mmol)and the benzene filtrate was concentrated under reduced pressure toobtain a reddish brown oily product (130 mg). This product was separatedand refined by thin-layer chromatography in the same way as in the aboveto obtain the pure compound (1') as colorless crystals (91 mg, 69%),m.p.: 127°-128.5° C., [α]_(D) ²⁰ =-44.0° (C=1.92, chloroform). Tworecrystallizations of this product from chloroform-ether gave anelemental analysis sample of the compound (1') in the form of colorlessneedle-like crystals with m.p.: 128°-129° C., [α]_(D) ²⁰ =-47.1°(C=1.11, chloroform) (S. Terashima, et al: Chem. Pharm. Bull. (Tokyo),27 2351 (1979)), m.p.: 128°-129° C., [α ]_(D) ²⁰ =-48.2° (C=0.982,chloroform)). IR ν_(max) ^(CHCl).sbsp.3 cm⁻¹ : 1710 (ketone). NMR (inCDCl₃)δ: 1.86-2.10 (2H, m,CH₂ C(OH)), 2.29 (3H, s, COCH₃), 2.70-3.10(4H, m, CH₂ CH₂ C(OH)CH₂), 3.58 (1H, s, OH), 3.72 (3H, s, OCH₃), 3.76(3H, s, OCH₃), 6.62 (2H, s, aromatic protons). The spectra of theseproducts agreed with those of the literature (S. Terashima, et al: Chem.Pharm. Bull (Tokyo), 27, 2351 (1979)).

What is claimed is:
 1. A process for producing2-(1'-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula,##STR37## which comprises reducing2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula, ##STR38##with the reducing agent obtained by reacting one equivalent of lithiumaluminum hydride with one equivalent of an optically activeN-substituted ephedrine of the formula ##STR39## (wherein R₁ is a C₁ -C₄alkyl or benzyl group and Ph is phenyl group)and two equivalents of anN-substituted aniline of the formula, ##STR40## (wherein R₂ is a C₁ -C₄straight-chain alkyl or phenyl group and Ph is phenyl group).
 2. Aprocess for producing(-)-2'-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of theformula, ##STR41## which comprises reducing2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene of the formula, ##STR42##with a reducing agent obtained by reacting one equivalent of lithiumaluminum hydride with one equivalent of (-)-N-(C₁ -C₄)alkylephedrineandtwo equivalents of an N-substituted aniline of the formula, ##STR43##(wherein R₂ is a C₁ -C₄ straight-chain alkyl or phenyl group and Ph isphenyl group).
 3. A process for producing(-)-2'-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene of theformula, ##STR44## which comprises reducing2-acetyl-5,8-dimethoxy-3,4-dihydro-naphthalene of the formula, ##STR45##with a reducing agent obtained by reacting one equivalent of lithiumaluminum hydride with one equivalent of (-)-N-methylephedrine and twoequivalents of an N-substituted aniline of the formula, ##STR46##(wherein R₂ is a C₁ -C₄ straight-chain alkyl or phenyl group and Ph isphenyl group).